Abstract | BACKGROUND: HYPOTHESIS: A three-dimensional (3D) culture system, by maintaining differential cellular organization that is typical of each tumor variant, may allow for the maintenance of particular hormone responses and thus be appropriate for the study of the effects of specific inhibitors of signaling pathways associated with disease progression. METHOD: PRINCIPAL FINDINGS:
LY294002, a PI3K/AKT pathway inhibitor, decreased both tumor growth in vivo and cell survival in Matrigel in MPA-independent tumors with higher AKT activity. Induction of cell death by anti- hormones such as ICI182780 and ZK230211 was more effective in MPA-dependent tumors with lower AKT activity. Inhibition of MEK with PD98059 did not affect tumor growth in any tested variant. Finally, while Matrigel reproduced differential responsiveness of MPA-dependent and -independent breast cancer cells, it was not sufficient to preserve antiprogestin resistance of RU486-resistant tumors. CONCLUSION: We demonstrated that the PI3K/AKT pathway is relevant for MPA-independent tumor growth. Three-dimensional cultures were useful to test the effects of kinase inhibitors on breast cancer growth and highlight the need for in vivo models to validate experimental tools used for selective therapeutic targeting.
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Authors | Maria Laura Polo, Maria Victoria Arnoni, Marina Riggio, Victoria Wargon, Claudia Lanari, Virginia Novaro |
Journal | PloS one
(PLoS One)
Vol. 5
Issue 5
Pg. e10786
(May 26 2010)
ISSN: 1932-6203 [Electronic] United States |
PMID | 20520761
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Estrogen Receptor alpha
- Hormones
- Phosphoinositide-3 Kinase Inhibitors
- Protein Kinase Inhibitors
- Receptors, Steroid
- Mifepristone
- Proto-Oncogene Proteins c-akt
- Mitogen-Activated Protein Kinase Kinases
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Topics |
- Animals
- Breast Neoplasms
(drug therapy, enzymology, pathology)
- Cell Culture Techniques
(methods)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Cell Separation
- Drug Resistance, Neoplasm
(drug effects)
- Enzyme Activation
(drug effects)
- Estrogen Receptor alpha
(metabolism)
- Female
- Hormones
- Mice
- Mice, Inbred BALB C
- Mifepristone
(pharmacology)
- Mitogen-Activated Protein Kinase Kinases
(antagonists & inhibitors)
- Phosphoinositide-3 Kinase Inhibitors
- Protein Kinase Inhibitors
(pharmacology, therapeutic use)
- Proto-Oncogene Proteins c-akt
(metabolism)
- Receptors, Steroid
(antagonists & inhibitors)
- Signal Transduction
(drug effects)
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